Triplications of chromosome 1p36.3, including the genes GABRD and SKI,are associated with a developmental disorder and a facial gestalt

Triplication of chromosomal region 1p36.3 is a rare genomic rearrangement. In this report, we delineate the phenotypic spectrum associated with 1p36.3 triplications. We describe four patients with microtriplications of variable size, but with a strong phenotypic overlap, and compare them to previously described patients with an isolated triplication or duplication of this region. The 1p36.3 triplication syndrome is associated with a distinct phenotype, characterized by global developmental delay, moderate intellectual disability, seizures, behavioral problems, and specific facial dysmorphic features, including ptosis, hypertelorism, and arched eyebrows. The de novo occurrence of these microtriplications demonstrates the reduced reproductive fitness associated with this genotype, in contrast to 1p36.3 duplications which are mostly inherited and can be associated with similar facial features but with a less severe developmental phenotype. The shared triplicated region encompasses four disease-related genes of which GABRD and SKI are most likely to contribute to the phenotype.     

The Low-Grade Lymphomas

The lymphomas comprise a spectrum of diseases with vast variation in histologic appearance, presentation and natural history, and response to therapy. At one end of the spectrum are the low-grade lymphomas (LGLs), indolent malignancies characterized by paradox. Despite an exceedingly low growth fraction, the LGLs are usually extensive at presentation, and yet they rarely involve privileged sites, such as cortical bone or central nervous system, and rarely destroy adjacent tissue. They are exquisitely responsive to many different therapeutic interventions, but responses to most agents are transient and similar. Finally, although survival of most LGL patients is measured in years, the course of the disease is punctuated by both transient and long-term responses to treatment, and also by spontaneous regression and transformation to more aggressive lymphomas in the absence of therapy, rendering the evaluation of the true impact of treatment quite difficult. The focus of this review is on the management of the LGLs, in particular the role of radiotherapy.     

Comparison of ambulatory and inpatient experiences in five specialties

This study compared medical student evaluations of ambulatory and inpatient components of third-year clerkships in internal medicine, obstetrics/gynaecology, paediatrics, psychiatry, and surgery. Seventy-two students completed evaluation questionnaires at the conclusion of each of five clerkships over 12 months. Although ambulatory and inpatient evaluations were comparable across all five specialties in several areas, ambulatory education was rated more favorably in scheduling, clear definition of student roles and responsibilities, appropriate supervision, timely and constructive feedback, being welcomed, and working in a non-threatening environment.Student feedback thus implied that ambulatory experiences were comparable to, or better than, inpatient experiences and suggests areas for improving clinical education in inpatient settings.     

Drinking water source and chlorination byproducts in Iowa. III. Risk of brain cancer.

The authors conducted a population-based case-control study in Iowa of 375 brain cancer patients and 2,434 controls. A postal questionnaire was used to gather information on lifetime residential history, sources of drinking water, beverage intake, and other potential risk factors. Exposure to chlorination byproducts in drinking water was estimated by combining questionnaire data with historical information from water utilities and trihalomethane levels in recent samples. The analysis included 291 cases (77.6%) and 1,983 controls (81.5%), for whom water quality information was available for at least 70% of lifetime years. Proxies represented 74.4% of cases. The mean number and mean duration of places of residence were comparable between direct and proxy respondents, suggesting little contribution to bias. After multivariate adjustment, odds ratios for brain cancer were 1.0, 1.1, 1.6, and 1.3 for exposure to chlorinated surface water of 0, 1-19, 20-39, and > or =40 years (p trend = 0.1). Among men, odds ratios were 1.0, 1.3, 1.7, and 2.5 (p trend = 0.04), and among women, 1.0, 1.0, 1.6, and 0.7 (p trend = 0.7)). Similar findings were found with estimates of average lifetime level of trihalomethanes. The association was stronger among men with above-median tap water consumption. These observations deserve further attention, especially in view of increasing glioma rates.     

Repeated use of computerized case simulations in a test format does not present a security risk

BACKGROUND: Computer-based examination formats permit evaluation of patient care strategies in a realistic context. Because such examinations are complex and difficult to develop, the same case simulations must often be used on multiple occasions. METHODS: To determine if repeated, serial administration of computerized case simulations influences performance, 8 simulations were administered over 2 consecutive years to 252 third-year medical students at the conclusion of 16 surgical clerkship rotations (8 per year). One-way analyses of variance were used to compare scores across rotations during the year and to compare scores between 2 consecutive academic years. Scheffe pairwise comparisons were used to identify trends within each academic year. RESULTS: The data demonstrate an increase in scores across rotations during the year. There is, however, no difference between scores in successive years. CONCLUSIONS: The data are consistent with an increase in knowledge during the course of the year, without evidence that test information transfer influences the performance of successive classes.     

Survival and outcome after endotracheal intubation for acute stroke

OBJECTIVE: To assess survival and functional outcome in patients endotracheally intubated after ischemic stroke (IS) or spontaneous intracerebral hemorrhage (ICH). BACKGROUND: Endotracheal intubation is both a necessary life support intervention and a measure of severity in IS or ICH. Knowledge of associated clinical variables may improve the estimation of early prognosis and guide management in these patients. METHODS: We reviewed 131 charts of patients with IS or ICH who were admitted to the Neurosciences Intensive Care Unit at Duke University Medical Center between July 1994 and June 1997 and required endotracheal intubation. Stroke risk factors, stroke type (IS or ICH) and location (hemispheric, brainstem, or cerebellum), circumstances surrounding intubation, neurologic assessment (Glasgow Coma Score [GCS] and brainstem reflexes), comorbidities, and disposition at discharge were documented. Survivors were interviewed for Barthel Index (BI) scores. RESULTS: Survival was 51% at 30 days and 39% overall. Variables that significantly correlated with 30-day survival in multivariate analysis included GCS at intubation (p = 0.03) and absent pupillary light response (p = 0.008). Increase in the GCS also correlated with improved functional outcome measured by the BI (p = 0.0003). In patients with IS, age and GCS at intubation predicted survival, and in patients with ICH, absent pupillary light response predicted survival. CONCLUSIONS: Predictors for mortality differ between patients with IS and ICH; however, decreased level of consciousness is the most important determinant of increased mortality and poor functional outcome. Absent pupillary light responses also correspond with a poor prognosis for survival, but further validation of this finding is needed.     

Activation of tyrosine receptor kinase plays a role in expression of long-term potentiation in the rat dentate gyrus

Long-term potentiation (LTP) in perforant path-granule cell synapses has been shown to be accompanied by an increase in glutamate release. The objective of this study was to examine the possibility that nerve growth factor (NGF), by activating tyrosine kinase, modulates glutamate release and, therefore, contributes to expression of LTP in dentate gyrus. The data indicate that NGF, in the presence of trans-1-aminocyclopentyl-1,3-dicarboxylate (ACPD), enhanced KCI-stimulated release and KCI-stimulated calcium influx in vitro and that these effects were blocked by the tyrosine receptor kinase (trk) inhibitor tyrphostin AG879. The data also indicate that NGF increased phosphorylation of trkA and the mitogen-activated protein kinase extracellular signal-regulated kinase (ERK) in dentate gyrus in vitro. In addition to its effects in vitro, tyrphostin AG879 inhibited the expression of LTP in perforant path-granule cell synapses and the accompanying increase in transmitter release. Analysis of phosphorylation of the two tyrosine kinase substrates trkA and ERK in synaptosomes prepared from untetanized and tetanized dentate gyrus revealed that LTP was associated with increased phosphorylation of both proteins; no evidence of such a change was observed in either tetanized or untetanized tissue prepared from tyrphostin-pretreated rats. These findings are consistent with the hypothesis that NGF, by interacting with trkA, triggers a sequence of tyrosine kinase-dependent phosphorylation steps that modulate glutamate release and calcium influx and impact on expression of LTP in dentate gyrus.     

Lysosomal dysfunction results in lamina-specific meganeurite formation but not apoptosis in frontal cortex

An inhibitor of cathepsins B and L was used to test if lysosomal dysfunction in cultured slices of rat frontal cortex induces pathological features that develop in the human cortex during aging and Alzheimer's disease (AD). Incubation for 6 days with N-CBZ-L-phenylalanyl-L-alanine-diazomethylketone (ZPAD) resulted in a massive proliferation of endosomes-lysosomes in all cortical layers. Slices additionally exposed to a washout of 4 days had numerous meganeurites, blister-like structures in the region of the axon hillock, in layer III but not in other cortical laminae. Meganeurites are a characteristic feature of the human frontal cortex after age 50 and are largely restricted to layer III. Tests for apoptosis were carried out at two intervals following meganeurite formation. TUNEL-labeled neurons were confined to layers II/III on the surface of the slices but there was no evidence for a ZPAD effect. In all, 6 days of lysosomal dysfunction reproduces characteristic effects of normal aging in neocortex without generating some key features of AD.